Wild‐type offspring of heterozygous prolactin receptor‐null female mice have maladaptive β‐cell responses during pregnancy

Key points Heterozygous prolactin receptor‐null mice (Prlr+/−) are glucose intolerant during pregnancy. Their wild‐type offspring are at greater risk of developing glucose intolerance during their own pregnancy. The impaired glucose tolerance of the offspring during her own pregnancy is associated with a lower β‐cell mass, as well as a reduction in expression of insulin receptor substrate‐2, Akt and Forkhead box D3 in the islets, in comparison to mice born to wild‐type mothers. Signalling molecules that mediate prolactin‐specific signals, such as Jak/Stat, tryptophan hydroxylase‐1, menin and Forkhead box M1, are expressed in comparable levels between wild‐type offspring derived from either wild‐type or heterozygous prolactin receptor‐null mothers. The glucose‐stimulated insulin secretory response during pregnancy is minimally affected in mice derived from heterozygous prolactin receptor‐null mothers. Abstract β‐Cell mass increases during pregnancy in adaptation to the insulin resistance of pregnancy. This increase is accompanied by an increase in β‐cell proliferation, a process that requires intact prolactin receptor (Prlr) signalling. Previously, it was found that during pregnancy, heterozygous prolactin receptor‐null (Prlr+/−) mice had lower number of β‐cells, lower serum insulin and higher blood glucose levels than wild‐type (Prlr+/+) mice. An unexpected observation was that the glucose homeostasis of the experimental mouse depends on the genotype of her mother, such that within the Prlr+/+ group, the Prlr+/+ offspring derived from Prlr+/+ mothers (Prlr+/+(+/+)) had higher β‐cell mass and lower blood glucose than those derived from Prlr+/− mothers (Prlr+/+(+/−)). Pathways that are known to regulate β‐cell proliferation during pregnancy include insulin receptor substrate‐2, Akt, menin, the serotonin synthetic enzyme tryptophan hydroxylase‐1, Forkhead box M1 and Forkhead box D3. The aim of the present study was to determine whether dysregulation in these signalling molecules in the islets could explain the maternal effect on the phenotype of the offspring. It was found that the pregnancy‐induced increases in insulin receptor substrate‐2 and Akt expression in the islets were attenuated in the Prlr+/+(+/−) mice in comparison to the Prlr+/+(+/+) mice. The expression of Forkhead box D3, which plays a permissive role for β‐cell proliferation during pregnancy, was also lower in the Prlr+/+(+/−) mice. In contrast, the pregnancy‐induced increases in phospho‐Jak2, tryptophan hydroxylase‐1 and FoxM1, as well as the pregnancy‐associated reduction in menin expression, were comparable between the two groups. There was also no difference in expression levels of genes that regulate insulin synthesis and secretion (i.e. glucose transporter 2, glucokinase and pancreatic and duodenal homeobox‐1) between these two groups. Taken together, these results suggest that the in utero environment of the Prlr+/− mother confers long‐term changes in the pancreatic islets of her offspring such that when the offspring themselves became pregnant, they cannot adapt to the increased insulin demands of their own pregnancy.

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